Highly stereoselective synthesis of C-(alkynyl)-pseudoglycals from δ-hydroxy-α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2006.05.159

An efficient and novel methodology for the synthesis of C-(alkynyl)-pseudoglycals from δ-hydroxy-α,β-unsaturated aldehydes has been developed.

Full text of DOI:10.1016/j.tetlet.2006.05.159

Tetrahedron Letters 47 (2006) 5269–5272
Highly stereoselective synthesis of C-(alkynyl)-pseudoglycals from
d-hydroxy-a,b-unsaturated aldehydesI
J. S. Yadav,* A. Krishnam Raju and V. Sunitha
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 April 2006; revised 18 May 2006; accepted 24 May 2006
Available online 13 June 2006
Abstract—An efficient and novel methodology for the synthesis of C-(alkynyl)-pseudoglycals from d-hydroxy-a,b-unsaturated alde-
hydes has been developed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Carbohydrates are important constituents of glycopro-
teins and glycolipids that are involved in numerous bio-
logical processes.1 C-Glycosides2 have been the subject
of considerable interest in carbohydrate, enzymatic
and metabolic chemistry, as well as in organic synthesis.
They are versatile chiral building blocks for the synthesis
of many biologically important natural products such as
palytoxin, spongistatin, halichondrin, etc.3 In addition,
they are potential inhibitors of carbohydrate processing
enzymes and are stable analogues of glycans involved in
important intra- and intercellular processes.4 In parti-
cular, C-(alkynyl)-glycosides are attractive due to the
presence of a triple bond that can be easily transformed
into other chiral molecules and carbohydrate analogues
such as ciguatoxin and tautomycin, etc.5 C-Glycoside
analogues have gained considerable attention in the past
two decades and to date, numerous methods have been
described for their synthesis.6 In general, 2,3-unsatu-
rated C-glycosides are prepared by C-glycosidation of
glycals using different nucleophiles involving Ferrier
rearrangement.7
gram aimed at developing the synthesis of C-glycoside
analogues8 of complex bioactive glycosides, we report
herein a novel and efficient method to access selectively
C-(alkynyl)-pseudoglycals from d-hydroxy-a,b-unsatu-
rated aldehydes and alkynyl silanes (Scheme 1). To the
best of our knowledge, no synthesis of C-(alkynyl)-
pseudoglycals from d-hydroxy-a,b-unsaturated alde-
hydes has been previously reported. In recent years,
indium reagents have emerged as mild and water-toler-
ant Lewis acids imparting high chemo-, regio- and stere-
oselectivity in various organic transformations.9
Compared to conventional Lewis acids, indium halides
have advantages of water stability, recyclability and
simplicity in operation. Indeed, such Lewis acids are
effective catalysts in promoting many fundamental
reactions including Diels–Alder reactions, Michael reac-
tions, Friedel–Crafts acylation reactions, Mukaiyama
aldol reactions and Sakurai allylation reactions. In addi-
tion, indium trihalides are found to be more effective
than conventional Lewis acids in promoting the cyana-
tion of ketones, thioacetalization of carbonyl com-
pounds and O-glycosidation under mild conditions.10
The synthesis of optically active compounds has posed
challenges directed towards new methodologies with
more practical sources. The development of effective
C-glycoside syntheses depends on the selective forma-
tion of only one anomer as the major reaction product
in good to excellent yield. As a part of an ongoing pro-
Initially, we attempted the reaction of d-hydroxy-enal
1a11 with phenyl(trimethylsilyl) acetylene using 5 mol %
of indium(III) bromide as a catalyst. Interestingly, the
R
R''
O
R'
InBr3
Keywords: C-Pseudoglycosides; Indium reagents; d-Hydroxy-a,b-un-
saturated aldehydes; Alkynylsilanes.
q IICT Communication No. 060406.
+
Me3Si
R
CHO
R'
CH2Cl2, r.t.
R''
OH
2
1
*
Corresponding
author.
Fax:
+91
40
27160512; e-mail:
Scheme 1.
yadavpub@iict.res.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.159

5270
J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 5269–5272
C-(alkynyl)-pseudoglycal product 2a was isolated in 91%
yield, the structure of the product 2a being verified by
1H NMR spectroscopic data.12,13 In a similar fashion,
various alkynyl silanes including aromatic and
aliphatic substituted acetylenes reacted smoothly with
aldehyde 1a under similar reaction conditions to afford
the corresponding C-(alkynyl)-glycals in good yields
(Table 1, entries a–h). No b-anomer was observed in
the 1H NMR spectra of the crude products. Encouraged
by these results, we turned our attention to other alde-
hydes. 5-Hydroxy-5-phenyl-(E)-2-pentenal 1b, prepared
from benzaldehyde and allyl bromide, reacted efficiently
in good yield and with high selectivity (Table 1, entry i).
Similarly aldehyde 1c, prepared from 1-decanal and allyl
bromide, reacted smoothly under the reaction condi-
tions with various alkynyl silanes to provide the corre-
sponding C-(alkynyl)-glycals in good yields and with
high selectivity (Table 1, entries j and k). Again 1H
NMR of the crude products indicated that no b-isomer
was present. Although aldehydes 1b and 1c were used as
racemates, optically pure products can be prepared from
the enantiopure aldehydes.
Table 1. Formation of C-(alkynyl)-pseudoglycals from d-hydroxy-a,b-unsaturated aldehydes and silyl acetylenes
Entry Silyl acetylene
d-(OH)-a,b-unsaturated aldehydes Time (h) Producta (2)
Yieldb (%)
91
OAc
Ph
H
O
Me3Si
Me3Si
Ph
a
0.5
1.0
AcO
AcO
AcO
AcO
1a
1a
OH
OH
O
O
SiMe3
OAc
OAc
O
O
O
O
H
SiMe3
b
85
AcO
AcO
H
H
Me3Si
AcO
AcO
c
d
e
2.0
2.0
3.0
90
89
90
AcO
AcO
1a
1a
OH
OH
O
O
OAc
OAc
Me3Si
Me3Si
AcO
AcO
( )2
H
AcO
AcO
( )2
AcO
1a
OH
O
OAc
OAc
( )3
O
O
Me3Si
Me3Si
H
H
AcO
AcO
f
3.5
3.5
85
75
( )3
AcO
AcO
1a
1a
1a
OH
OH
O
O
OTBDPS
AcO
AcO
g
OTBDPS
OTBDPS
OAc
O
Me3Si
H
h
i
1.0
5.5
78
70
AcO
AcO
AcO
OTBDPS
OH
O
( )3
H
Ph
Ph
O
Me3Si
Me3Si
Me3Si
( )3
1b
OH
O
( )3
H
O
( )6
( )6
j
7.0
7.0
65
67
( )3
1c
OH
OH
O
Ph
H
O
( )6
Ph
k
( )6
1c
O
a All products were characterized by 1H, 13C NMR, IR and mass spectroscopy.
b Isolated and unoptimized yields.

J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 5269–5272
5271
OH
OH
OH
..
In(III)
R'
R'
R'
O
H
H
H
R"
R"
+
R''
+
O
O
H
In(III)
3
1
4
R'
R'
R
R'
O
..
+
R'
O
O
O
R''
R''
In(III)
R''
O
R''
SiMe3
R'
R
2
Me3Si
+
6
5
7
Scheme 2. Possible mechanism for the reaction.
However, ortho-hydroxy trans-cinnamaldehyde and
phenyl (trimethylsilyl) acetylene did not give the desired
product under the present reaction conditions. Further-
more, a,b-unsaturated aldehydes not possessing a d-
hydroxyl group did not yield the desired products. It is
important to mention that simple unprotected acetyl-
enes, such as phenyl acetylene, did not yield the desired
products under the reaction conditions. A possible
mechanism is illustrated in Scheme 2 which involves
activation of the aldehyde by indium(III) bromide and
subsequent formation of the oxonium intermediate 6
in which stereoelectronic and/or steric factors drive the
direction of the incoming silyl acetylene. A possible cat-
ionic charge would develop on the b-carbon in 7, which
is highly stabilized by the silicon atom.14 Elimination of
the trimethylsilyl group results in the formation of the
product 2. This mechanism better explains the a-stereo-
chemistry of the resultant products than the alternative
mechanism where C–C bond formation precedes C–O
bond formation. This process is highly regio- and stere-
oselective affording C-(alkynyl)-pseudo-glycals from d-
hydroxy-a,b-unsaturated aldehydes and silyl acetylenes.
yl)-pseudoglycals from simple d-hydroxy-a,b-unsatu-
rated aldehydes and alkynyl silanes in a highly regio-
and stereoselective manner.
Acknowledgement
A.K.R. and V.S. thank CSIR, New Delhi, for the award
of fellowships.
References and notes
1. Dwek, R. A. Chem. Rev. 1996, 96, 683–720.
2. The term C-glycoside is short for carbon-glycoside.
3. Horita, K.; Sakurai, Y.; Nagasawa, M.; Hachiya, S.;
Tonemistu, O. Synlett 1994, 43–45.
4. Weatherman, R. V.; Mortell, K. H.; Chervenak, M.;
Kiessling, L. L.; Toone, E. J. Biochem. 1996, 35, 3619–
3624.
5. (a) Isobe, M.; Nishizawa, R.; Hosokawa, S.; Nishikawa,
T. Chem. Commun. 1998, 2665–2677; (b) Hosokawa, S.;
Isobe, M. Synlett 1995, 1179–1180; (c) Jiang, Y.; Ichik-
awa, Y.; Isobe, M. Synlett 1995, 285–288; (d) Hosokawa,
S.; Isobe, M. Synlett 1996, 351–352.
There are several advantages in the use of indium tribr-
omide as catalyst for this transformation, which include
high yields of products, clean reaction profiles, short
reaction times, high selectivity and recoverability of
the catalyst. Among various catalysts, indium tribro-
mide was found to be most effective in terms of conver-
sion and selectivity. For example, treatment of aldehyde
1a with phenyl(trimethylsilyl) acetylene in the presence
of 5 mol % of InBr3 or 5 mol % of InCl3 for 1 h afforded
91% and 75% yields, respectively.
6. (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545–8599;
(b) Postema, M. H. D. C-Glycoside Synthesis; CRC Press:
Boca Raton, 1995; (c) Levy, D. E.; Tang, C. The
Chemistry of C-Glycosides; Pergamon: Tarrytown, NY,
1995; (d) Togo, H.; He, W.; Waki, Y.; Yokoyama, M.
Synlett 1998, 700–717; (e) Smoliakova, I. P. Curr. Org.
Chem. 2000, 4, 589–608; (f) Du, Y.; Linhardt, R. J.;
Vlahov, I. R. Tetrahedron 1998, 54, 9913–9959; (g)
Ichikawa, Y.; Isobe, M.; Konobe, M.; Goto, T. Carbo-
hydr. Res. 1987, 171, 193–199; (h) Isobe, M.; Nishizawa,
R.; Hosokawa, S.; Nishikawa, T. Chem. Commun. 1998,
2665–2676; (i) Saeeng, R.; Sirion, U.; Sahakitpichan, P.;
Isobe, M. Tetrahedron Lett. 2003, 44, 6211–6215.
7. (a) Ferrier, R. J. J. Chem. Soc. (C) 1964, 5443–5449; (b)
Ferrier, R. J.; Ciment, D. M. J. Chem. Soc. (C) 1966,
441–445; (c) Ferrier, R. J.; Prasad, N. J. Chem. Soc. (C)
1969, 570–574; (d) Ferrier, R. J.; Prasad, N. J. Chem. Soc.
(C) 1969, 581–586; (e) Danishefsky, S.; Keerwin, J. F.
J. Org. Chem. 1982, 47, 3803–3805.
8. (a) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K.; Rao, C. V.
Tetrahedron Lett. 2002, 43, 5437–5440; (b) Yadav, J. S.;
Reddy, B. V. S.; Rao, C. V.; Reddy, M. S. Synthesis 2003,
247–250.
9. (a) Takahiro, T.; Li, C. J.; Chan, T. H. Tetrahedron 1999,
55, 11149–11176; (b) Babu, G.; Perumal, P. T. Aldrichim.
Acta 2000, 33, 16–22; (c) Ghosh, R. Indian J. Chem. 2001,
40B, 550–557.
This method is simple, convenient and highly stereose-
lective affording C-(alkynyl)-pseudoglycals in good
yields from simple d-hydroxy-a,b-unsaturated aldehydes
and alkynyl silanes. In addition, this method is also use-
ful for the direct synthesis of 4-deoxy C-glycoside ana-
logues (Table 1, entries i–k). This method facilitates
the introduction of sugar nuclei as a chiral pool as well
as alkynyl moiety in one-pot, which makes it an efficient
pathway for producing C-(alkynyl)-pseudoglycals which
can be further modified to give biologically important
natural products.
In summary, we have developed an efficient strategy to
selectively synthesize simple as well as complex C-(alkyn-

5272
J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 5269–5272
10. (a) Bandini, M.; Cozzi, G. P.; Melchiorre, P.; Umani-
Ronchi, A. Tetrahedron Lett. 2001, 42, 3041–3043; (b)
Babu, B. S.; Balasubramanian, K. K. Tetrahedron Lett.
2000, 41, 1271–1274; (c) Ceschi, M. A.; Felix, L. A.;
Peppe, C. Tetrahedron Lett. 2000, 41, 9695–9699.
(KBr): m 3024, 2125, 1745, 1577, 1402, 1219, 1092 cmꢁ1
;
HRMS calcd for C18H18O5 314.1154, found 314.1149.
25
Compound 2d: (a-anomer): liquid; ½aꢀD ꢁ82.5 (c 3.5,
CHCl3); 1H NMR (200 MHz, CDCl3): d 0.95 (t, 3H,
J = 6.2 Hz), 1.30–1.50 (m, 4H), 2.01 (s, 6H), 2.12 (t, 2H,
J = 6.3 Hz), 4.00 (ddd, 1H, J = 3.0, 6.5, 9.0 Hz), 4.18 (dd,
1H, J = 3.0, 12.1 Hz), 4.21 (dd, 1H, J = 3.0, 12.1 Hz), 4.95
(m, 1H), 5.25 (dd, 1H, J = 1.9, 9.0 Hz), 5.60 (dd, 1H,
J = 1.9, 10.3 Hz), 5.82 (dt, 1H, J = 2.0, 10.3 Hz); 13C
NMR (proton decoupled, 50 MHz, CDCl3): d 13.2, 20.6,
21.2, 21.8, 29.3, 31.7, 63.1, 65.0, 69.7, 76.0, 77.6, 87.4,
124.6, 130.0, 170.1, 170.7; IR (KBr): m 2967, 2217, 1731,
1463, 1372, 1238, 1046, 758 cmꢁ1; HRMS calcd for
C16H22O5 294.1467, found 294.1470. Compound 2i
(a-anomer): liquid; 1H NMR (200 MHz, CDCl3): d 0.93
(t, 3H, J = 6.4 Hz), 1.22–1.60 (m, 8H), 2.20–2.36 (m, 4H),
4.90 (dd, 1H,J = 5.2, 9.8 Hz), 4.95 (d, 1H, J = 1.5 Hz), 5.71
(ddd, 1H, J = 2.3, 3.7, 10.5 Hz), 5.82 (dtd, 1H, J = 1.5, 3.0,
10.5 Hz), 7.22–7.40 (m, 5H); 13C NMR (proton decoupled,
50 MHz, CDCl3): d 13.7, 21.2, 21.8, 28.7, 29.2, 31.6,
36.2, 65.2, 72.0, 77.1, 85.4, 122.3, 125.6, 128.2, 128.4,
129.3, 131.2; IR (KBr): m 2972, 2213, 1453, 1369, 1242,
768 cmꢁ1; HRMS calcd for C19H24O 268.1827, found
268.1822.
11. Gonzalez, F.; Lesage, S.; Perlin, A. S. Carbohydr. Res.
1975, 42, 267–274.
12. General procedure: A mixture of 3-formyl-1-[1-hydroxy-2-
methylcarbonyloxy-(1R)-ethyl]-(1S,2E)-2-propenyl acetate
1a (5 mmol), phenyl (trimethylsilyl) acetylene (5 mmol)
and indium tribromide (5 mol %) in dichloromethane
(10 mL) was stirred at room temperature. After complete
conversion, as indicated by TLC, the reaction mixture was
diluted with water (10 mL) and extracted with dichloro-
methane (2 · 15 mL). The organic layers were dried over
anhydrous Na2SO4 and purified by column chromatogra-
phy on silica gel (Merck, 100–200 mesh, ethyl acetate–
hexane, 1:9) to afford the pure alkynyl C-glycoside deriv-
ative. The aqueous layer was concentrated in vacuo and the
catalyst recovered, quantitatively. Spectroscopic data for
selected compounds: Compound 2a (a-anomer): liquid;
20
½aꢀD ꢁ105.7 (c 1.0 CHCl3); 1H NMR (200 MHz, CDCl3): d
2.03 (s, 6H), 4.10 (ddd, 1H, J = 3.0, 6.5, 12.0 Hz), 4.19 (dd,
1H, J = 3.0, 12.0 Hz), 4.21 (dd, 1H, J = 3.0, 12.1 Hz), 5.15
(d, 1H, J = 1.4 Hz), 5.25 (dd, 1H, J = 2.2, 8.8 Hz), 5.78 (dt,
1H, J = 1.4, 10.7 Hz), 5.90 (ddd, 1H, J = 1.4, 2.2, 10.7 Hz),
7.30–7.20 (m, 3H), 7.40–7.38 (m, 2H); 13C NMR (50 MHz,
CDCl3): d 20.6, 20.9, 63.0, 64.4, 64.8, 70.0, 84.7, 86.6,
122.2, 125.4, 128.2, 128.6, 129.1, 131.7, 170.1, 170.7; IR
13. Our spectral data for products 2a–h (1H NMR, 13C NMR,
FTIR, EIMS and optical rotation) were identical with
those for the reported compounds.6g–i,8
14. Takahiro, T.; Isobe, M. Tetrahedron Lett. 1992, 33, 7911–
7914, and references cited therein.